Trametinib Improves Survival in Low-Grade Serous Ovarian Cancer

A phase 2/3 trial found that patients with low-grade serous ovarian cancer treated with trametinib had improved survival over the standard of care.

Patients with recurrent low-grade serous ovarian cancer treated with trametinib (Mekinist) had significantly improved survival compared with the standard of care (SOC), according to results of the phase 2/3 GOG-281/LOGS trial (NCT02101788) published in The Lancet Oncology.

At the time of the primary analysis, there were 217 progression-free survival (PFS) events in a cohort of 260 patients, of which 101 occurred in the trametinib group and 116 in the SOC group. Median PFS in the trametinib group was 13.0 months (95% CI, 9.9-15.0) vs 7.2 months (95% CI, 5.6-9.9) in the SOC group (HR, 0.48; 95% CI, 0.36-0.64; P <.0001).

The median duration of follow-up was 31.5 months in the trametinib group vs 31.3 months for SOC. At the time of data cutoff, 229 patients (88%) had discontinued treatment because of disease progression, toxicity, patient choice, other, or death.

Patients were randomized 1:1 to receive oral trametinib at 2 mg once daily or either paclitaxel at 80 mg/m2 intravenously over 1 hour on days 1, 8, and 15 of 28-day cycles; pegylated liposomal doxorubicin at 40 to 50 mg/m2 intravenously over 1 hours on day 1 of 28-day cycles; topotecan (Hycamtin) at 4 mg/m2 intravenously over 1 hour on days 1, 8, and 15 of 28-day cycles; oral letrozole at 2.5 mg once daily; or oral tamoxifen at 20 mg twice daily.

A post-hoc analysis of 87 patients showed a longer median PFS of 15.0 months (95% CI, 7.7-23.1) if they were given trametinib vs 10.6 months (95% CI, 6.5-12.8) if given letrozole (HR, 0.58; 95% CI, 0.36-0.95; one-sided P = .0085).

For patients receiving trametinib, the overall response rate (ORR) was 26% with an additional 59% of patients having stable disease for a minimum of 8 weeks. The ORR for the overall SOC group was 6% (odds ratio, 5.4; 95% CI, 2.4-12.2; P <.0001) and the stable disease rate was 71% (95% CI, 92-130). ORRs for individual therapies were letrozole at 14%, paclitaxel at 9%, pegylated liposomal doxorubicin at 3%, tamoxifen at 0%, and topotecan at 0%. Median duration of response was 13.6 months (95% CI, 8.1-18.8) in the trametinib group and 5.9 months (95% CI, 2.8-12.2) in the SOC group.

At data cutoff, 111 patients had died, with a median OS of 37.6 months (95% CI, 32.0-not eveluable) in the trametinib group and 29.9 months (95% CI, 23.5-51.6) in the SOC group (HR, 0.76; 95% CI, 0.51-1.12; one-sided P = .056).

Dose reductions occurred in 156 of 1365 cycles (11%) of trametinib treatment, with 90 patients having at least 1 dose reduction during the study. Additionally, 38 patients had 2 dose reductions and of those, 14 withdrew because of disease progression.

The median PFS for patients in the SOC group who crossed over to the trametinib group was 10.8 months (95% CI, 7.3-12.0) with an ORR of 15% (95% CI, 7.0%-22.0%). Of these patients, 66 progressed or died on trametinib of whom 43 had a longer time to disease progression with the agent than with the previous SOC therapy.

The most common grade 3/4 adverse effects (AEs) with trametinib were acneiform or maculo-papular skin rash (13%), anemia (13%), and hypertension (12%). The most frequent for those in the SOC group were abdominal pain (17%), nausea (11%), and anemia (10%).

AEs of special interest in the trametinib group were pneumonitis (2%), QTc prolongation (2%), left ventricular systolic dysfunction (2%), retinal vascular disorder (2%), and retinal tear (1%). There were no grade 5 AEs attributed to trametinib. AEs of special interest in the SOC group had included grade 3 left ventricular systolic dysfunction (1%) and grade 3 decreased ejection fraction (1%).

Reference

Gershenson DM, Miller A, Brady WE, et al. Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial. Lancet. 2022;399(10324):541-553. doi:10.1016/S0140-6736(21)02175-9